Essential thrombocythemia (ET)

  • Method:
  • Anticoagulant:
  • Recommendation:
  • Method:
    Cytomorphology
  • Anticoagulant:
    EDTA
  • Recommendation:
    obligatory
  • Method:
    Immunophenotyping
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative
  • Method:
    Chromosome analysis
  • Anticoagulant:
    Heparin
  • Recommendation:
    facultative
  • Method:
    FISH
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative
  • Method:
    Molecular genetics
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    obligatory

Essential (or primary) thrombocythemia (ET) is a chronic myeloproliferative, BCR-ABL1 negative neoplasm (MPN). It is characterized by an increased proliferation of the megakaryocytic lineage in the bone marrow as well as by a dysfunction and a progressive proliferation of platelets in peripheral blood. Due to the lack of specific markers, the diagnosis is not always clear, and therefore secondary thrombocytosis should be excluded. Secondary thrombocytosis is mainly caused by inflammation or iron deficiency.

Definition and characteristics of Essential Thrombocythemia

Up to one third of patients are symptom-free at initial diagnosis of ET, as the diagnosis is often established during a routine blood test. The majority of patients remain symptom-free for several years and have an almost normal life expectancy. In the course of the disease, however, complications such as microcirculation disorders in the sense of circulatory disorders in the hands and feet, thromboembolic complications and bleeding may occur. The risk of thrombosis is increased in the presence of ET. Most cases occur in patients over 60 years of age and is one of the leading causes of death in ET (Elliott et al. 2005). In a small proportion of patients, the disease progresses to polycythaemia vera (PV), post-ET myelofibrosis or myelodysplastic syndrome (MDS) or secondary acute leukemia.

The annual incidence of ET has not been established with certainty and is based on the estimate of the Polycythaemia Vera Study Group (PVSG) for the European region and the USA: 0.2 - 2.3 / 100,000 inhabitants. It occurs at the median age of 50-60 years and is slightly more common in women than in men. Nevertheless, almost 20 percent of patients with essential thrombocythemia are 40 years or younger, and in some cases children and young adults may also be affected (Swerdlow et al. 2017).

Classification of Essential Thrombocythemia

According to the WHO classification 2017, ET belongs to the so-called BCR-ABL1 negative myeloproliferative neoplasms. The clinical differentiation within the MPN is based on the detection of clonal thrombocytosis (see also criteria for essential thrombocytosis). In the peripheral blood smear, platelets are morphologically altered in 90% of patients: enlarged and/or different sizes. A subdivision into subgroups was not made within the WHO classification. However, it should be noted that there are currently no specific disease markers, molecular or otherwise, that uniquely diagnose ET, so a diagnosis should always be based on a combination of clinical, molecular genetic and bone marrow histological findings.

ET WHO Classification 2017

Diagnostic criteria for essential thrombocythemia

Major criteria

  • Platelet count ≥ 450x109/L
  • Bone marrow histology: Proliferation mainly of the megakaryocyte lineage, with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei; no significant increase or left shift in neutrophil granulopoiesis or erythropoiesis. Very rarely a minor (grade 0-1) increase in reticulin fibres
  • WHO criteria for BCR-ABL1-positive CML, PV, PMF or other myeloid neoplasms are not met
  • JAK2, CALR, or MPL mutation

Minor criteria

  • Presence of clonal marker or

  • Absence of evidence of reactive thrombocytosis

The diagnosis ET requires all four major or the first three major and one minor criterion.

Essential Thrombocythemia: Diagnostics

Prognosis and risk stratification in Essential Thrombocythemia

Within chronic myeloproliferative diseases, ET has the most favorable course. Affected patients usually have a normal life expectancy and, especially in the first 10 years, show no difference in quality of life compared to a healthy control population. However, after this decade, a more frequent occurrence of thrombotic events is observed (Wolanskyj et al. 2006). ET should be specifically distinguished from prefibrotic PMF (pre PMF), which was introduced by the WHO in 2001 as a separate class within the MPN. According to the criteria of the Polycythaemia Vera Study Group, some of these pre PMF patients would be classified as ET patients, but have a slightly less favorable course compared to ET (Thiele et al. 2003). Since the probability of fibrotic or leukemic transformation is very small (< 1%, Malecki et al. 2016), the prognostic course of ET is mainly determined by the occurrence of thrombosis and severe bleeding (incidence: 11-39%, Pósfai et al. 2016). Accordingly, most prognostic systems rely on the identification of specific risk factors that can be used to detect patients at risk of thrombosis and bleeding at an early stage. Initially known risk factors include

  • History of known thromboembolic complications or severe bleeding

  • Age over 60 years (it is discussed to raise the age to 65 years, i.e. to take more account of the biological age)

  • Platelet count higher than 1.500.000/µl

Within the ET, two risk groups were initially established and later three and four risk groups respectively. Initially, the above mentioned parameters age and thromboembolic history were the most relevant prognostically.

In subsequent studies, further thrombotic risk factors were investigated in addition to the conventional factors (age and history of thrombosis). These include cardiovascular risk factors (e.g. arterial hypertension, diabetes, obesity and nicotine abuse), leukocytosis and the presence of a JAK2 V617F mutation and its allelic load. Barbui et al. have created an international prognosis system for thrombotic risk factors using a multi-variant analysis in 2012, which was published under the name IPSET (see Table 2). Low risk patients had a thrombosis-free survival of 87% after 15 years, while the high risk group showed a 50% probability of thrombosis-free survival in the first 7 years after diagnosis. The medium risk patients showed similar values to the low risk group during the first 10 years and approached the high risk curve in the following 5 years.

Table 2: ‘International Prognostic Score of thrombosis in essential thrombocythemia’ (IPSET-thrombosis)

(Barbui et al. 2012)

Risik factor

HR

Score

Age > 60 years

1.50

1

Cardiovascular risk factors

1.56

1

Previous thrombosis

1.93

2

JAK2 V617F

2.04

2

Low risk

0 - 1

Intermediate risk

2

High risk

≥ 3

The advantage of this new system was that patients could be classified even more precisely and specifically. For example, patients who had been assigned to the high-risk class using conventional parameters (age and symptoms) could be reclassified into the intermediate or even the low risk group. For example: age > 60 years, but no history of thromboembolic events, no cardiovascular risk factors and no JAK2 V617F mutation, would have been high risk in the past, but is now assigned to the low risk class. The IPSET score was validated in a later study in 2016 in 585 ET patients and was refined to include another risk group (see Table 3, Haider et al. 2016). In 2018, the IPSET was applied to a pre-PMF cohort and successfully evaluated to assess the risk of thrombosis in pre-PMF patients (Guglielmelli et al. 2018).

Table 3: Validation of the revised 'International Prognostic Score of thrombosis in essential thrombocythemia (IPSET-thrombosis)'

(Haider et al. 2016)

Risik factors

Risk

Age ≤ 60 years
No history of thrombosis
JAK2 wild type

Very low

Age ≤ 60 years
No history of thrombosis
JAK2 mutation

Low

Age > 60 years
No history of thrombosis
JAK2 wild type

Intermediate

History of thrombosis or
Age > 60 years and JAK2 mutation

High

Cytogenetic Prognostic Factors in Essential Thrombocythemia

Since cytogenetic abnormalities are detected in only a small percentage of ET patients, cytogenetic data have not found a major role or weighting in the establishment of scoring systems. For example, less than 10% of patients show cytogenetic abnormalities at first diagnosis (Panani et al. 2006, Gangat et al. 2009). Among the most frequently detected aberrations are anomalies of chromosome 1, trisomy 8 and trisomy 9, and deletions in the long arm of chromosome 13 and chromosome 20. Furthermore, these studies have shown that cytogenetic abnormalities occur during transformation into acute leukemia, but not during transformation into myelofibrosis (Panani et al. 2006, Gangat et al. 2009). In a further study, it was shown that, in contrast to PV and PMF, cytogenetic abnormalities at the time of initial diagnosis had neither an influence on the disease progression in terms of transformation into acute leukemia nor a significant influence on general or leukemia-free survival (Suleiman et al. 2016). However, more studies are needed to more clearly evaluate cytogenetics and its influence on ET.


Molecular Genetic Prognostic Factors in Essential Thrombocythemia

Because the prognosis of ET patients is highly dependent on the risk of thrombosis, no major scoring system - such as the MIPSS70+ for PMF - involving clinical, cytogenetic and molecular genetic prognostic factors has yet been introduced (Tefferi et al. 2108). JAK2 mutation can be detected in about 50% of ET patients, which is also frequently observed in all other MPNs. Due to the frequency of the JAK2 mutation, the prognostic relevance of the JAK2 mutation was investigated. However, studies have shown controversial results: an association between an existing JAK2 mutation and a higher Hb and leukocyte count and thus a significantly higher risk of thrombosis has been described (Campbell et al. 2005, Finazzi et al. 2006). Further studies, however, showed that the JAK2 mutation does not appear to be associated with the incidence of thromboembolic events (Antonioli et al. 2005, Carobbio et al. 2007). These differences may be due to: insufficient clinical criteria to adequately differentiate ET and PV patients, different patient selection and study design, and sole focus on qualitative JAK2 V617F expression rather than quantitative allelic load. Therefore, in subsequent studies, the allelic load was investigated. 2-4% of patients with ET have a homozygous JAK2 mutation. It was shown that patients with a homozygous mutation had a significantly higher risk to get thromboembolic events compared to heterozygous mutated or wild type patients. The higher the allelic load, the higher the risk of thrombosis (Kittur et al. 2007, Vannucchi et al. 2007, Antonioli et al. 2008). In addition to the JAK2 mutation, a CALR mutation is detected in approximately 20% of all ET patients. Calreticulin is a chaperone protected protein involved in differentiation, apoptosis and cell division. Compared to the JAK2 mutation, patients with a CALR mutation showed a lower risk of thrombosis (Torregrosa et al. 2016). However, MPL mutations occur in only 5% of patients, and no precise data on the risk of thrombosis in this patient group are known. The number of patients in whom none of the three "driver mutations" could be detected ("triple-negative") is estimated at 10-25%. These patients also showed an increased risk of thrombosis (Ju et al. 2018).

In addition to the above-mentioned "driver mutations", further studies investigated "non-driver mutations" during the course of the disease and their influence on overall survival as well as the probability of transformation into secondary myelofibrosis or acute leukemia. The most frequent mutations besides the already mentioned "driver mutations" JAK2/CALR/MPL were mutations in the genes ASXL1 (20%), TET2 (11%), DNMT3A (7%) and SF3B1 (5%). For other genes the following frequencies were found: SRSF2: 2%, EZH2: 2%, U2AF1: 1%, RUNX1: 1% and TP53: 2% (Tefferi et al. 2019). Table 5 lists the mutations examined by Tefferi et al. that showed an unfavorable influence on overall survival (OS), leukemia-free survival (LFS) and myelofibrosis-free survival (MFFS).

Table 4: "Non-driver mutations" and their prognostic significance

(Tefferi et al. 2019)

Mutations

Adverse effect on OS

SF3B1, SRSF2, EZH2, U2AF1

Adverse effect on LFS

SRSF2, EZH2, TP53, RUNX1

Adverse effect on MFFS

SF3B1, U2AF1


OS: Overall survival,
LFS:
Leukemia-free survival,
MFFS:
Myelofibrosis-free survival.

You may also be interested in

Career

As a rapidly growing, innovative medical laboratory, we are always looking for bright minds to help us bring new and more effective therapies to patients around the world.

Learn more

Services

Do you have questions about sample submission, analyses performed or findings? Here you will find contact details, contact persons and our most frequently asked questions (FAQs).

Learn more

Quality management

We have been certified according to national and international standards since 2009 and have successfully maintained these accreditations.

Learn more